Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism
Abstract Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However,...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-024-00735-3 |
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| author | Yangxia Tan Jiawei Li Shiyan Zhang Yonglei Zhang Zhiyi Zhuo Xiaodan Ma Yue Yin Yanling Jiang Yao Cong Guoyu Meng |
| author_facet | Yangxia Tan Jiawei Li Shiyan Zhang Yonglei Zhang Zhiyi Zhuo Xiaodan Ma Yue Yin Yanling Jiang Yao Cong Guoyu Meng |
| author_sort | Yangxia Tan |
| collection | DOAJ |
| description | Abstract Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle. |
| format | Article |
| id | doaj-art-981e3fbdb2fd4aa29ff0f26ea666ac65 |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-981e3fbdb2fd4aa29ff0f26ea666ac652024-12-01T12:09:24ZengNature Publishing GroupCell Discovery2056-59682024-11-0110111110.1038/s41421-024-00735-3Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanismYangxia Tan0Jiawei Li1Shiyan Zhang2Yonglei Zhang3Zhiyi Zhuo4Xiaodan Ma5Yue Yin6Yanling Jiang7Yao Cong8Guoyu Meng9Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityNational Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of ScienceShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityAbstract Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle.https://doi.org/10.1038/s41421-024-00735-3 |
| spellingShingle | Yangxia Tan Jiawei Li Shiyan Zhang Yonglei Zhang Zhiyi Zhuo Xiaodan Ma Yue Yin Yanling Jiang Yao Cong Guoyu Meng Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism Cell Discovery |
| title | Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism |
| title_full | Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism |
| title_fullStr | Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism |
| title_full_unstemmed | Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism |
| title_short | Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism |
| title_sort | cryo em structure of pml rbcc dimer reveals cc mediated octopus like nuclear body assembly mechanism |
| url | https://doi.org/10.1038/s41421-024-00735-3 |
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